J. Neurochem. (2012) 120 (Suppl. 1), 9–21.
β‐Amyloid precursor protein (APP) is a critical factor in the pathogenesis of Alzheimer’s disease (AD). APP undergoes post‐translational ...proteolysis/processing to generate the hydrophobic β‐amyloid (Aβ) peptides. Deposition of Aβ in the brain, forming oligomeric Aβ and plaques, is identified as one of the key pathological hallmarks of AD. The processing of APP to generate Aβ is executed by β‐ and γ‐secretase and is highly regulated. Aβ toxicity can lead to synaptic dysfunction, neuronal cell death, impaired learning/memory and abnormal behaviors in AD models in vitro and in vivo. Aside from Aβ, proteolytic cleavages of APP can also give rise to the APP intracellular domain, reportedly involved in multiple types of cellular events such as gene transcription and apoptotic cell death. In addition to amyloidogenic processing, APP can also be cleaved by α‐secretase to form a soluble or secreted APP ectodomain (sAPP‐α) that has been shown to be mostly neuro‐protective. In this review, we describe the mechanisms involved in APP metabolism and the likely functions of its various proteolytic products to give a better understanding of the patho/physiological functions of APP.
Asymmetric one‐carbon homologation or ring expansion of ketones with formal insertion of carbene intermediate, is a challenging but useful strategy to construct a complex skeleton. Sc(III) and chiral ...ligands have been employed in this regard. However, due to flexible conformations and a variety of stereo models, the origin of stereochemistry remains ambiguous. Density functional theory (DFT) calculations were carried out to explore the interactions that control the stereoselectivity of a Sc(III)‐catalyzed asymmetric homologation. The trans influence of counterions was found to affect the coordination mode of ketone to Sc(III), and consequently affect the stereoselectivity.
DFT study of Sc(III)‐catalyzed asymmetric homologation of ketones with diazo compounds revealed a new coordination mode of substrates which was rationalized by the trans influence. The origin of stereo‐selectivity was explored based on the coordination mode. A promising new strategy to adjust stereo‐selectivity by trans influence was proposed.
Disclosed here is the first geminal (gem‐) hydroborative cyclization of enynes. Different from known hydroborative cyclizations, this process adds hydrogen and boron to the same position, leading to ...a new reaction mode. With Cp*RuCl4 as catalyst, a range of gem‐hydroborated bicyclic products bearing a cyclopropane unit could be rapidly assembled from simple enyne substrates. Control experiments and density functional theory (DFT) calculations provided important insights into the reaction mechanism. Notably, two major competing pathways may operate with substrate‐dependence. 1,6‐Enynes favor initial oxidative cyclometalation to form a ruthenacyclopentene intermediate prior to engaging hydroborane, while other enynes (e.g., 1,7‐enynes) that lack strong propensity toward cyclization prefer initial alkyne gem‐(H,B)‐addition to form an α‐boryl ruthenium carbene followed by intramolecular olefin cyclopropanation. This process also represents the first ruthenium‐catalyzed enyne hydroborative cyclization.
Different from the previously known hydroborative cyclizations that add hydrogen and boron to opposite sides of an enyne, the proper choice of a ruthenium catalyst alters this propensity to a new addition mode, geminal hydroborative cyclopropanation. Two possible mechanisms are operative, which are substrate‐dependent based on DFT studies.
A large amount of evidence has demonstrated the revolutionary role of nanosystems in the screening and shielding of biological systems. The explosive development of interfacing bioentities with ...programmable nanomaterials has conveyed the intriguing concept of nano–bio interfaces. Here, recent advances in functional biointegrated devices through the precise programming of nano–bio interactions are outlined, especially with regard to the rational assembly of constituent nanomaterials on multiple dimension scales (e.g., nanoparticles, nanowires, layered nanomaterials, and 3D‐architectured nanomaterials), in order to leverage their respective intrinsic merits for different functions. Emerging nanotechnological strategies at nano–bio interfaces are also highlighted, such as multimodal diagnosis or “theragnostics”, synergistic and sequential therapeutics delivery, and stretchable and flexible nanoelectronic devices, and their implementation into a broad range of biointegrated devices (e.g., implantable, minimally invasive, and wearable devices). When utilized as functional modules of biointegrated devices, these programmable nano–bio interfaces will open up a new chapter for precision nanomedicine.
Recent advances in biointegrated devices are attributed to the precise programming of nano–bio interactions, especially with regard to the rational assembly of constituent nanomaterials on multiple dimension scales. Their respective intrinsic merits are leveraged for different functions, such as multimodal theragnostics and smart therapeutics delivery, permitting their implementation into a variety of functional biointegrated devices, including flexible nanoelectronic devices.
A commercially available cobalt complex Cp*CoIII(CO)I2 has been found to effectively catalyze the diamination of α‐alkyl styrenes with anilines under a mild reaction condition, using dioxygen as the ...oxidant. This reaction features a reasonably good substrate scope of amines and a good functional group tolerance. Preliminary mechanistic studies have shown that Cp*CoIII(CO)I2 alone can promote the diamination reaction.
Posttranslational modifications (PTMs) of proteins are responsible for sensing and transducing signals to regulate various cellular functions and signaling events. S-nitrosylation (SNO) is one of the ...most important and universal PTMs. With the avalanche of protein sequences generated in the post-genomic age, it is highly desired to develop computational methods for timely identifying the exact SNO sites in proteins because this kind of information is very useful for both basic research and drug development. Here, a new predictor, called iSNO-PseAAC, was developed for identifying the SNO sites in proteins by incorporating the position-specific amino acid propensity (PSAAP) into the general form of pseudo amino acid composition (PseAAC). The predictor was implemented using the conditional random field (CRF) algorithm. As a demonstration, a benchmark dataset was constructed that contains 731 SNO sites and 810 non-SNO sites. To reduce the homology bias, none of these sites were derived from the proteins that had Formula: see text pairwise sequence identity to any other. It was observed that the overall cross-validation success rate achieved by iSNO-PseAAC in identifying nitrosylated proteins on an independent dataset was over 90%, indicating that the new predictor is quite promising. Furthermore, a user-friendly web-server for iSNO-PseAAC was established at http://app.aporc.org/iSNO-PseAAC/, by which users can easily obtain the desired results without the need to follow the mathematical equations involved during the process of developing the prediction method. It is anticipated that iSNO-PseAAC may become a useful high throughput tool for identifying the SNO sites, or at the very least play a complementary role to the existing methods in this area.
Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor expressed in microglia in the brain. A soluble form of TREM2 (sTREM2) derived from proteolytic cleavage of the ...cell surface receptor is increased in the preclinical stages of AD and positively correlates with the amounts of total and phosphorylated tau in the cerebrospinal fluid. However, the physiological and pathological functions of sTREM2 remain unknown. Here, we show that sTREM2 promotes microglial survival in a PI3K/Akt-dependent manner and stimulates the production of inflammatory cytokines depending on NF-κB. Variants of sTREM2 carrying AD risk-associated mutations were less potent in both suppressing apoptosis and triggering inflammatory responses. Importantly, sTREM2 delivered to the hippocampi of both wild-type and
-knockout mice elevated the expression of inflammatory cytokines and induced morphological changes of microglia. Collectively, these data indicate that sTREM2 triggers microglial activation inducing inflammatory responses and promoting survival. This study has implications for the pathogenesis of AD and provides insights into targeting sTREM2 pathway for AD therapy.
Inflammatory bowel disease (IBD) is a type of chronic inflammatory disorder that interferes with the patient's lifestyle and, in extreme situations, can be deadly. Fortunately, with the ...ever-deepening understanding of the pathological cause of IBD, recent studies using nanozyme-based materials have indicated the potential toward effective IBD treatment. In this review, the recent advancement of nanozymes for the treatment of enteritis is summarized from the perspectives of the structural design of nanozyme-based materials and therapeutic strategies, intending to serve as a reference to produce effective nanozymes for moderating inflammation in the future. Last but not least, the potential and current restrictions for using nanozymes in IBD will also be discussed. In short, this review may provide a guidance for the development of innovative enzyme-mimetic nanomaterials that offer a novel and efficient approach toward the effective treatment of IBD.
Aberrant glucose metabolism and immune evasion are recognized as two hallmarks of cancer, which contribute to poor treatment efficiency and tumor progression. Herein, a novel material system ...consisting of a glucose and TEMPO (2,2,6,6‐tetramethylpiperidin‐1‐yl)oxyl) at the distal ends of PEO‐b‐PLLA block copolymer (glucose‐PEO‐b‐PLLA‐TEMPO), is designed to encapsulate clinical therapeutics CUDC101 and photosensitizer IR780. The specific core–shell rod structure formed by the designed copolymer renders TEMPO radicals excellent stability against reduction‐induced magnetic resonance imaging (MRI) silence. Tumor‐targeting moiety endowed by glucose provides the radical copolymer outstanding multimodal imaging capabilities, including MRI, photoacoustic imaging, and fluorescence imaging. Efficient delivery of CUDC101 and IR780 is achieved to synergize the antitumor immune activation through IR780‐mediated photodynamic therapy (PDT) and CUDC101‐triggered CD47 inhibition, showing M1 phenotype polarization of tumor‐associated macrophages (TAMs). More intriguingly, this study demonstrates PDT‐stimulated p53 can also re‐educate TAMs, providing a combined strategy of using dual tumor microenvironment remodeling to achieve the synergistic effect in the transition from cold immunosuppressive to hot immunoresponsive tumor microenvironment.
This study presents new insights on CUDC101 in the reprogramming of tumor‐associated macrophages toward antitumor M1 phenotype by CD47 inhibition with a glucose‐contained magnetic resonance imaging‐capable supramolecular rod‐like micelle, and phototriggered p53 by codelivery of IR780 can achieve the synergistic effect in the transition from cold immunosuppressive to hot immunoresponsive tumor microenvironment.
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